Exercise participation is an important determinant of cognitive health, particularly in aging. In fact, sedentary behavior has been singled out as the greatest modifiable risk factor causing cognitive decline and Alzheimer's Disease in the US, and ranks third worldwide. Despite the importance of physical activity and exercise, the exercise parameters that provide optimal cognitive health are not well defined, particularly with respect to the frequency and duration of exercise needed. Our data and others suggest that the exercise conditions that activate the underlying neurobiological mechanisms that enhance cognitive function can be flexible, and allow for intermittent and spaced exercise bouts. We propose the novel hypothesis that exercise establishes a type of molecular memory for the exercise stimulus, which regulates the frequency and duration of subsequent intermittent exercise that is needed to maintain cognitive benefits. The molecular memory remains during a defined temporal window, such that subsequent exercise (even low-level exercise normally sub-threshold to enhance long-term memory formation) can capitalize on the neurobiological events established by the initial experience of exercise, thus maintaining the benefits of exercise on cognitive function. We hypothesize that epigenetic mechanisms are fundamental for the molecular memory phenomenon, and serve to alter transcriptional processes through histone modifications to create stable changes in neuronal plasticity and giving rise to stable changes in behavior. Our goal in this proposal is to define the exercise parameters that establish a molecular memory, investigate the underlying mechanisms that enable exercise to more efficiently promote enhanced cognition, and explore if pharmaceutical manipulation can extend the molecular window established by exercise. Because benefits of exercise for improving cognition, particularly hippocampal function, rely in large part from induction of the key plasticiy molecule `brain-derived neurotrophic factor' (BDNF), we focus on BDNF induction and epigenetic modifications that control BDNF regulation. We propose three Aims. Aim 1 - Determine the effective exercise patterns and molecular memory temporal windows that result in long-term memory formation. Aim 2 - Determine the histone modification patterns resulting from exercise that establish a molecular memory for BDNF expression. Aim 3 - Determine if cognitive benefits of exercise can be prolonged by pharmacological manipulation of the epigenetic molecular memory established by exercise, using a novel selective histone deacetylase 3 (HDAC3) inhibitor. Overall, our research in this proposal will serve as a foundation for ultimately translating to humans the exercise parameters needed to maintain enhanced cognitive function.